The use of functional neuroimaging techniques (e.g. functional magnetic resonance imaging-- fMRI) in combination with neuropsychological activation paradigms has served to deepen our understanding of regional brain dysfunction in psychiatric disorders, but the application of such types of functional studies to patients with bipolar disorder has been minimal. Bipolar disorder is one of the top ten causes of disability worldwide, yet the neurophysiologic basis of the disorder remains unknown. In this proposal, we will use novel computational anatomy techniques to develop average anatomic representations for coregistration with fMRI images in bipolar subjects and compare this to normal controls. Using such methods, we hope to clarify whether orbitofrontal gray and/or white matter structural deficits are primarily associated with the reduction in neural activity seen in fMRI. Specifically, we will 1) assess disease-specific alterations in neural function in the orbitofrontal cortex using fMRI tasks that activate this region;2) explore the underlying structural etiology of orbitofrontal hypofunction using novel techniques to measure gray and white matter;and 3) determine the relationship between alteration in gray matter (cortical thickness) or white matter volume and neural function. This has not, to our knowledge, been attempted in the bipolar population. This exploration may clarify the neural/biologic underpinnings of bipolar disorder. The discovery of specific anatomic abnormalities that are associated with clear functional consequences may direct the pursuit of targeted neuropharmacologic development and lead to better treatments for patients with bipolar disorder. PUBLIC HEALTH RELEVANCE: The neurophysiologic basis of bipolar disorder remains unknown. This application proposes to compare the brain functional deficits in persons with bipolar disorder (observed during the performance of neuropsychological tasks during functional MRI) to gray and white matter volume data obtained from structural MRI. We hope to clarify whether gray and/or white matter structural deficits are associated with the reduction in neural activity seen in fMRI and in turn clarify the neural/biologic underpinnings of bipolar disorder.